What is Hyperpolarization?
Hyperpolarization is a process that dramatically increases the nuclear spin polarization of specific atomic nuclei, far beyond the levels achieved at thermal equilibrium in a typical MRI scanner. This enhancement can boost the MRI signal intensity by 10,000 to over 100,000 times, making it possible to visualize metabolic pathways and physiological processes in vivo that were previously undetectable with conventional MRI.
Commonly Used Hyperpolarized Nuclei
- Carbon-13 (¹³C): The most widely used nucleus for metabolic imaging, particularly with agents like pyruvate to study energy metabolism in cancer, cardiac disease, and other conditions.
- Nitrogen-15 (¹⁵N): Offers potential for studying nitrogen metabolism, including processes like the urea cycle or amino acid metabolism.
- Xenon-129 (¹²⁹Xe): An inert noble gas primarily used for pulmonary imaging (ventilation and gas exchange) and emerging applications in functional neuroimaging via dissolved-phase detection.
Hyperpolarization Techniques
- Dynamic Nuclear Polarization (DNP): The most common method for ¹³C and ¹⁵N. It involves cooling a sample containing the agent and a polarizing radical to very low temperatures (~1 Kelvin) in a high magnetic field (3–7T) and using microwave irradiation to transfer the high polarization of electron spins to the nuclear spins.
- Parahydrogen-Induced Polarization (PHIP): Utilizes chemically prepared parahydrogen (a specific spin state of H₂) to transfer polarization to target nuclei through chemical reactions. PHIP is generally faster, less expensive, and technically simpler than DNP but is limited to molecules compatible with the required chemistry.
- Spin Exchange Optical Pumping (SEOP): The primary technique for hyperpolarizing noble gases like ¹²⁹Xe and ³He. It involves using laser light to polarize electron spins of an alkali metal vapor (like Rubidium), which then transfer their polarization to the noble gas nuclei via collisions (spin exchange).
Important Concepts and Terms
- Solid and Liquid-State Polarization (primarily for DNP):
- Solid-state polarization: The DNP process occurs with the sample in a frozen, solid state at ultra-low temperatures.
- Rapid Dissolution: To make the agent injectable, the hyperpolarized solid sample is rapidly dissolved in a superheated, sterile solvent just before injection, creating a hyperpolarized liquid solution. This liquid state is necessary for administration and subsequent MRI.
- Signal Decay (T₁ Relaxation): The hyperpolarized state is non-equilibrium and decays back towards the much lower thermal equilibrium state with a characteristic time constant (T₁). This T₁ is relatively short (seconds to a few minutes in vivo), meaning the enhanced signal is transient and non-renewable. This necessitates rapid injection, fast imaging sequences, and careful RF pulse strategies.
- Flip Angle: The angle through which the net magnetization is tipped by a radiofrequency (RF) pulse. In hyperpolarized MRI, small flip angles (e.g., 5°–30°) are typically used. Because each RF pulse consumes some of the non-renewable hyperpolarized magnetization, small flip angles help preserve the signal for longer, allowing for dynamic imaging of metabolic conversion.
- B₁ Map: A map showing the spatial variations in the actual strength of the transmitted RF field (B₁). Accurate B₁ mapping is crucial for calibrating the RF pulses to achieve the intended flip angles across the region of interest, which is essential for reliable quantification of metabolic rates.
Imaging Sequences and Protocols
- Fast Spectroscopic Imaging Sequences: Specialized MRI sequences are required to capture both the spatial distribution and the chemical identity (frequency shift) of the hyperpolarized agent and its metabolic products rapidly before the signal decays. Examples include:
- Chemical Shift Imaging (CSI): Acquires a full spectrum from each voxel.
- Spectral-Spatial (SPSP) Pulses: Selectively excite specific metabolites and spatial locations.
- Echo Planar Imaging (EPI) based methods: Often combined with spectral encoding (e.g., flyback EPI-CSI, spiral CSI) for speed.
- Vendor Platforms (e.g., Bruker, GE, Philips, Siemens): Major MRI vendors offer research sequences and protocols adapted for hyperpolarized imaging, often integrated within their software platforms (like Bruker’s ParaVision). These facilitate acquisition setup, often including specialized RF pulses and reconstruction algorithms.
Polarization Equipment
- DNP Polarizers: Instruments (e.g., GE SPINlab™ or HyperSense®, Oxford Instruments Hyperpolariser) that perform Dynamic Nuclear Polarization, cooling samples to ~1K in a high magnetic field and applying microwaves before rapidly dissolving the sample for injection. These are complex systems typically found in specialized research centers.
- SEOP Polarizers: Devices specifically designed for polarizing noble gases using Spin Exchange Optical Pumping, often purpose-built for lung imaging or other ¹²⁹Xe/³He applications.
Practical Hyperpolarized MRI Agents & Applications
- 1-¹³C-Pyruvate: The most widely studied agent. Following injection, its conversion to 1-¹³C-Lactate is often elevated in tumors (Warburg effect) and can indicate tissue ischemia or metabolic dysfunction in the heart and other organs. Conversion to ¹³C-Alanine and ¹³C-Bicarbonate provides further metabolic insights.
- ¹³C-Urea: Generally considered metabolically inert over the short imaging window. Its distribution is primarily limited to the vascular and interstitial space shortly after injection, making it useful as a perfusion marker to assess blood flow and delivery, often used as a reference alongside metabolic agents.
- ¹³C-α-Ketoglutarate (αKG): Probes mitochondrial metabolism, particularly the Krebs cycle and related pathways. Its conversion can indicate enzymatic activity (e.g., IDH mutations in gliomas) or oxidative stress, relevant in cancer, cardiovascular, and neurological diseases.
- Other ¹³C Agents: Bicarbonate (for pH mapping), Fumarate (cell death/necrosis), Alanine, Glutamine, etc., are under investigation for various specific metabolic questions.
Hyperpolarized Xenon MRI
- ¹²⁹Xe Lung Imaging: Inhaled hyperpolarized ¹²⁹Xe gas provides exceptionally high signal from the lung airspaces, enabling high-resolution MR imaging of ventilation. Furthermore, as xenon dissolves into the lung tissue and pulmonary capillary blood, the signal from this dissolved phase can be detected separately (due to its different chemical shift). Imaging both the gas and dissolved phases allows for regional assessment of gas exchangefunction, which is impaired in diseases like COPD, pulmonary fibrosis, and pulmonary hypertension.
- ¹²⁹Xe Dissolved-Phase Imaging (Beyond Lung): Xenon that dissolves in the blood is transported systemically. Researchers are exploring the potential to use the signal from ¹²⁹Xe dissolved in blood and tissues like the brain or kidneys to probe regional blood flow, perfusion, and potentially tissue function/composition. This is an emerging area compared to lung imaging.
Conclusion
Hyperpolarized MRI is a rapidly evolving field that overcomes the inherent sensitivity limitations of conventional MRI for certain nuclei, enabling real-time visualization of cellular metabolism and physiological processes. Understanding the fundamental concepts of polarization, the properties of different nuclei and agents, the specialized techniques and hardware involved, and the unique challenges (like signal decay) is crucial for radiologists aiming to interpret or utilize this powerful technology in research and future clinical applications.